Historically, metastatic melanoma has been one of the most treatment refractory cancers. For decades, no drug demonstrated an overall survival (OS) benefit. However, recently the situation radically changed. Melanoma has emerged as a “model” tumor for which innovative therapeutic strategies have demonstrated significant efficacy. Two strategies, immunotherapy and targeted therapy, opened new treatment avenues, leading in 2011 to US and European approval of two landmark drugs: the anti-BRAF agent vemurafenib (ZelborafTM) and the anti-CTLA-4 monoclonal antibody ipilimumab (YervoyTM). This year, two additional targeted agents — another anti-BRAF drug, dabrafenib (TafinlarTM), and for the first time, an anti-MEK agent, trametinib (MekinistTM), were approved in the US. The MEK pathway represents a new complementary therapeutic target that could greatly expand opportunities for overcoming treatment resistance and lengthening lives.

The Molecular Age

The molecular classification of melanoma has played a key role in changing our approach to treatment of advanced disease. It is now a core part of diagnostic and therapeutic strategies. Melanoma is the cancer that carries the highest number of somatic mutations, with an average of 30 per Mb (megabase pair). Analysis of the spectrum of these mutations shows a clear enrichment for C->T or G->A transitions at pyrimidine dinucleotide sites, reinforcing the premise that damaging UV rays are a major melanoma risk factor.1

The identification of a mutation in exon 15 of the BRAF gene in 50-70 percent of melanomas was the catalyst for molecular classification.2 Since then, additional somatic mutations, most resulting in activation of either the MAPK (mitogen-activated-protein kinases) pathway or the PI3 kinase pathway, have been identified. Aberrant activation of the MAPK pathway occurs in more than 65 percent of melanomas.

BRAF Inhibitors

BRAF is a serine/threonine kinase belonging to the RAF family, which includes two additional enzymes, ARAF and CRAF (RAF1).3 BRAF is downstream of RAS proteins and upstream of MEK and ERK proteins on the MAPK pathway, which is involved in the response to transmembrane cellular growth factors. A recurrent gain-of-functionV600E BRAF mutation is present in 50-70 percent of melanomas. Downstreamfrom RAS and RAF proteins on the same MAPK pathway, the MEK1 and MEK2 proteins are found; encoded by the MAP2K1 and MAP2K2 genes, respectively, they harbor activating mutations in 8 percent of melanomas.4

Vemurafenib was approved in 2011 as a first-line treatment for patients with unresectable or metastatic melanoma harboring the V600E BRAF mutation, based on a Phase III trial of 675 subjects in which patients receiving vemurafenib had significantly improved overall survival compared to those on dacarbazine, and median progression-free survival (PFS) of 5.3 months versus 1.6 months for those receiving dacarbazine.5 Vemurafenib patients produced a 48 percent objective response rate vs. 5 percent for dacarbazine. Responses became evident clinically as well as on PET scans within 1–2 weeks of initiating treatment. The most common adverse events were arthralgia, fatigue, and cutaneous manifestations such as rash, photosensitivity, and squamous cell carcinoma (SCC) of the keratoacanthoma type.

New BRAF inhibitors are being developed, and findings suggest comparable clinical efficacy. Dabrafenib was FDAapproved this year based on a Phase III clinical trial in which dabrafenib-treated patients with advanced metastatic or unresectable melanoma had 4.51 months of progression-free survival (PFS), versus 2.7 months PFS for chemotherapy patients. The dabrafenib patients had a 51 percent objective response rate, including good signs of efficacy in patients with brain metastases.6,7 Dabrafenib may also have a better efficacy/toxicity profile than vemurafenib, with patients demonstrating almost no photosensitivity and fewer keratoacanthomas and SCCs (7 percent, versus 20-30 percent with vemurafenib).

However, there are two major concerns with all BRAF therapies thus far. The most challenging is the short median duration of clinical responses, with most patients relapsing 4 to 12 months after therapy is initiated. Various mechanisms of drug resistance have been described, most reflecting primary resistance present from the beginning and expressed over the course of treatment, likely due to clonal heterogeneity of the tumors. Numerous distinct resistance mechanisms that can reactivate the MAPK pathway or use other proliferation pathways have been identified.8

The second downside of BRAF inhibitors is that, paradoxically, they can activate the MAPK pathway in cells devoid of BRAF mutation. This unwanted side effect probably requires an additional somatic event such as a UV-induced RAS mutation on the signaling pathway. Such an event could explain the appearance of squamous cell neoplasias as well as the new melanomas observed in patients receiving BRAF inhibitors.9,10,11,12 For this reason, the risk of internal cancer should not be overlooked, and patients should be closely monitored, especially with potential adjuvant use.

MEK Inhibitors

Trametinib

Potent inhibitors of MEK1 and MEK2 proteins downstream on the same MAPK pathway are also being developed [Figure 1]. The most advanced, trametinib, a non-allosteric cAMP (cyclic adenosine monophostate) inhibitor, was recently FDA-approved for metastatic or unresectable melanoma patients whose tumors express BRAF V600E or V600K gene mutations. Approval was based on the randomized Phase III metric trial including 322 patients with advanced melanomas harboring such V600 mutations. Eligible patients previously treated with at most one line of therapy excluding BRAF or MEK inhibitors were randomly assigned to receive either trametinib orally b.i.d. or chemotherapy (dacarbazine or paclitaxel). Crossover to the trametinib arm was allowed for patients whose disease progressed in the chemotherapy arm.13 The primary endpoint was improved PFS, but the researchers also looked at response rate, safety, and overall survival.

A statistically significant improved PFS of 4.8 months was achieved in trametinib-treated patients compared to 1.5 months in the chemotherapy patients. More surprisingly, though 51 patients (47 percent) initially treated with chemotherapy crossed over to the trametinib arm, improved overall survival was noted — 6-month survival of 81 percent in the trametinib arm vs. 67 percent in the chemotherapy arm, with a 46 percent reduced risk of death in the trametinib patients. The objective response rate in the trametinib arm was 22 percent, versus 8 percent in the chemotherapy arm. The most common adverse events with trametinib were skin rashes, usually of a papulo-pustular type, with less than 8 percent at grade 3 or 4. Diarrhea, peripheral edema, and fatigue, though common, reached grade 3 or 4 in less than 6 percent of cases. Potential serious adverse events involving the retina or myocardia were rare and mostly reversible.

Trametinib was thus the first MEK inhibitor to demonstrate therapeutic benefit in a Phase III randomized trial.

Figure 1: Schematic representation of the MAP kinase signalization pathway aberrantly activated by mutations, amplifications, or deletions in more than 65 percent of melanomas. The new targeted anti-BRAF and anti-MEK therapies inhibit the key promoters in this pathway, halting cancerous cell growth, proliferation, and survival.

Selumetinib

In a recent, randomized Phase II trial of 91 treatment-naïve patients with metastatic BRAF-mutated melanoma, those receiving a combination of the MEK inhibitor selumetinib and dacarbazine demonstrated a trend towards a survival benefit, with a median OS of 13.9 months, vs. 10.5 months among patients receiving dacarbazine alone. More notably, patients receiving selumetinib plus dacarbazine had a significant PFS of 5.6 months, compared to just three months for the dacarbazine monotherapy patients.14 The safety profile of selumetinib and dacarbazine combined was consistent with that of each drug separately.

The Future: Combination Therapies

Trametinib is thus far approved only as a monotherapy, and it may be a welcome option as such for BRAF-mutated patients who cannot tolerate BRAF inhibitors. But it appears that the main use will be in combination with BRAF inhibitors. Initial results of an early three-arm Phase II randomized trial evaluating two doses of trametinib and dabrafenib in combination vs. dabrafenib monotherapy were recently published. Response rate and PFS were higher in the high-dose combination, with 76 percent objective responses in the combination arm versus 53 percent in the dabrafenib monotherapy arm, and a PFS of 9.4 months vs. 5.8 months for the monotherapy. The duration of response was also longer — 10.5 months in the combination group and 5.6 months in the dabrafenib arm. As preclinical studies had predicted, the paradoxical activation of the MAP kinase pathway during anti-BRAF monotherapy was much less frequently observed with the combination therapy. This was borne out by a much lower occurrence of SCCs and keratoacanthomas – just 7 percent of the patients undergoing combination therapy vs. 19 percent in patients receiving dabrafenib alone.15 Based on these convincing early results, GlaxoSmithKline has already filed for FDA approval of the two-drug combination, with final-stage Phase III data expected late this year.

Combination therapies using other MEK and BRAF inhibitors are now being tested against BRAF inhibitor monotherapy in several Phase III trials. One critical question is whether anti-MEK agents will be effective in patients who fail anti-BRAF monotherapy. Unfortunately, it seems that anti-MEK therapy alone will not be the answer; among 40 patients receiving trametinib after BRAF inhibitor resistance, the response rate was only 5 percent, with a median PFS of just 1.8 months.16

We do not have statistically significant data concerning the efficacy of the BRAF/MEK inhibitor combination in patients resistant to BRAF inhibitors, but preliminary studies on a small population of patients have reported some responses and disease stabilization.

Conclusions

Although immense progress has recently been achieved in melanoma treatment, questions must be addressed. We do not yet know, for example, whether anti-MEK agents will have a significant role used alone, or if their use in combination with anti-BRAF agents will become the new standard of care for targeted therapy of BRAF-mutant melanoma. We also have to evaluate these and other drugs used sequentially.

Researchers fully understand that overcoming advanced melanoma will be a long, complex battle. Multiple mutations in melanoma lead to multiple disease pathways and many routes for the cancer cells to escape targeted drugs. Both intra-pathway and inter-pathway drug combinations will probably be met by secondary resistance, and in the near future, most patients will relapse. It will therefore be of fundamental importance to combine the targeted therapeutic strategies with immunotherapies.

Editor’s Note: This story originated with a presentation by Dr. Robert at The Skin Cancer Foundation’s 14th World Congress on Cancers of the Skin in Sao Paulo, Brazil.